NEW YORK (Reuters Health) - Proton pump inhibitors (PPIs) are associated with an increased risk of gastric cancer even in patients who have had Helicobacter pylori (HP) infection eradicated, according to a population-based study in Gut.

"Long-term PPIs should be used with caution in those with HP infection, even after HP eradication," Dr. Wai Keung Leung of Queen Mary Hospital in Hong Kong, one of the study's authors, told Reuters Health by email. "However, the absolute risk difference is not that high and should not deter physicians from prescribing PPIs when necessary, particularly short-term use."

Curing HP infection reduces gastric cancer risk by up to 47%, but some people do develop the disease after HP eradication, Dr. Leung and his team note in their report, online October 31. PPIs suppress acid secretion, which can make atrophic gastritis worse in susceptible patients, they add, while the drugs also cause secretion of the growth factor gastrin. A meta-analysis found a 43% increased risk of gastric cancer in PPI users, the team adds, but research has not looked at HP-infected and HP-negative patients separately.

The researchers looked at medical records for 63,397 patients who had been prescribed clarithromycin-based triple therapy from 2003 to 2012. During a median follow-up of 7.6 years, 153 (0.24%) developed gastric cancer. There were 3,271 PPI users and 21,729 patients on histamine-2 receptor antagonists (H2RAs).

Patients on PPIs were significantly more likely to develop gastric cancer (hazard ratio, 2.44) than those not taking the drugs, but H2RAs were not associated with increased risk. The longer a patient had been using PPIs, the greater their increased gastric cancer risk (HR, 5.04 for a year or longer, 6.65 for two years or more, and 8.34 for three years or longer).

Guidelines recommend eradicating HP infection before a patient starts taking PPIs long-term, the researchers note, but there are no data to suggest that this will help prevent gastric cancer.

"Despite successful H. pylori eradication, which would significantly reduce the risk of gastric cancer, those who continue to take long-term PPIs have about 2.4-fold increase in risk of gastric cancer development," Dr. Leung said. "This increase in risk is not found in those taking a H2-receptor antagonist, a weaker acid-suppressive agent. The risk also increases with the duration of PPI treatment."

PPI users in the study who had not received HP eradication were at lower gastric cancer risk compared to those who received HP eradication. "This group consisted of largely HP-negative subjects, suggesting that the increase in risk among PPI users is largely related to HP-related gastric inflammation, which would persist despite successful HP eradication if they continue to take PPIs," Dr. Leung explained.

PPIs on their own may not be enough to increase cancer risk, unless patients have previous HP infection, Dr. Leung said. He and his colleagues are now interested in investigating other gastric cancer risk factors after HP eradication.